Value Proposition
· Human disease relevance: Recapitulate key dystroglycanopathy features including cobblestone lissencephaly, neuronal migration defects, and muscular dystrophy
· Complementary severity spectrum: B3gnt1 mutants survive to adulthood with mild symptoms; Crppa mutants show severe early phenotypes
· Drug discovery ready: Enable screening for therapeutic compounds targeting dystroglycan pathway restoration
· Embryonic insights: Enable study of critical developmental windows when dystroglycan dysfunction causes brain malformations
· Research advantage: Hypomorphic B3gnt1 model allows longitudinal studies impossible with lethal knockout models
Unmet Need
Dystroglycanopathies are a group of severe neurodevelopmental disorders caused by defective glycosylation of dystroglycan during embryonic development, resulting in congenital brain malformations, intellectual disability, epilepsy, and muscle weakness. Current research lacks appropriate animal models that recapitulate the specific glycosylation defects occurring during critical embryonic developmental windows and the variable disease severity seen in patients. Existing knockout models often result in early embryonic lethality, preventing study of disease progression and therapeutic testing. Therefore, there is a strong need for precise genetic models with variable phenotypic severity that faithfully reproduce the spectrum of human dystroglycanopathy symptoms.
Technology Description
Researchers at Johns Hopkins have developed mouse models to study dystroglycanopathies—congenital disorders caused by defective dystroglycan glycosylation that result in brain malformations, epilepsy, and muscular dystrophy. They identified mutations in B3gnt1 and Crppa that create complementary disease phenotypes: B3gnt1 mutants survive to adulthood with mild muscular dystrophy, while Crppa mutants show severe cobblestone lissencephaly and perinatal lethality. These models span the full spectrum of dystroglycanopathy severity, providing valuable platforms for understanding disease mechanisms and testing therapeutic interventions.
Stage of Development
· These mutant mouse strains are available on Jax Lab’s repository:
o Jax # 022018 C3.B6-B3gnt1m1Ddg/J
o Jax # 022019 C3.B6-Ispdm1Ddg/J
Data Availability
· n/a
Publication
Kevin M. Wright, Krissy A. Lyon, Haiwen Leung, Daniel J. Leahy, Le Ma, David D. Ginty. Dystroglycan Organizes Axon Guidance Cue Localization and Axonal Pathfinding. Neuron. 2012. https://doi.org/10.1016/j.neuron.2012.10.009.
